The present invention relates to the use of complex lipids as additives stabilizing against a decrease in lipolytic activity under the influence of moisture to water-soluble pharmaceutical preparations of digestive enzyme mixtures which contain protease/lipase mixtures, in particular pancreatin, and which are suitable for preparing aqueous solutions for continuous introduction into the gastrointestinal tract by means of tubes. The invention furthermore relates to water-soluble pharmaceutical preparations of digestive enzyme mixtures containing lipases and proteases, especially of pancreatin-containing digestive enzyme mixtures, which are stabilized by complex lipids against a decrease in lipolytic activity under the influence of moisture, and which are suitable for preparing aqueous solutions which can be introduced into the gastrointestinal tract of mammals or humans by means of a tube.
A deficiency of digestive enzymes may occur in mammals, especially humans, for example caused by a pathological change in the pancreas resulting from chronic pancreatitis, digestive insufficiency after stomach operations, hepatic or biliary disorders. It is already known that deficiency manifestations of these types can be treated by administration of non-endogenous pancreatin-containing digestive enzyme mixtures such as, for example, pancreatic enzymes, especially pancreatin, which may optionally also contain added lipases. The pancreatic enzymes are normally administered orally in the form of solid preparations. In order for the administered enzyme mixtures taken orally not to undergo unwanted irreversible denaturation in the stomach by gastric acid and proteolytic enzymes, such as pepsin, present therein, it is necessary to provide the enzyme mixtures with a coating resistant to gastric fluid. A coating of this type permits the intact enzyme mixtures to pass through the stomach to their site of action, the duodenum, where the protective layer is degraded by the neutral to slightly alkaline conditions prevailing therein, and the enzymes are released. Like the endogenous pancreatic enzymes of the healthy person, the orally administered enzymes are able to display their enzymatic effects, in particular amylolytic, lipolytic and proteolytic activities, there.
Solid pancreatin formulations of this type which can be coated with a film resistant to gastric fluid and are in the form of micropellets are described, for example, in Bodecker et al., U.S. Pat. No. 5,378,462 (=DE 4,227,385), the disclosure of which is incorporated herein by reference.
For patients with digestive insufficiency, in particular patients confined to bed with prolonged digestive insufficiency such as, for example, chronic pancreatic insufficiency, it would be desirable to administer non-endogenous digestive enzymes also over a lengthy period in liquid form, for example by continuous administration by means of a tube, in place of solid dosage forms.
It has not heretofore been possible to provide liquid dosage forms of pancreatin-containing digestive enzyme mixtures, in particular of pancreatin, because liquid aqueous preparations of such enzyme mixtures are not stable over a lengthy period. It has been found, in particular, that the activity of the lipases present in the mixture decreases rapidly in the presence of water due to proteolytic attack by the proteases which are likewise present in the mixture, such as trypsin or chymotrypsin. Thus, there may be substantial loss of lipase activity in aqueous pancreatin preparations within a very short time depending on the external conditions (temperature, pH).
In order to be suitable for continuous introduction into the gastrointestinal tract by administration by means of a tube, aqueous solutions of digestive enzyme mixtures containing lipases and proteases, in particular of pancreatin-containing digestive enzyme mixtures, must be stable for a period of several hours, for example 8 hours. In particular, no particles blocking the tube must be produced or present in the solutions. An essential requirement for solutions of this type is that an activity of all the digestive enzymes present therein which is as high and as constant as possible is maintained throughout the administration period. It is furthermore necessary for solutions suitable for continuous gastrointestinal administration that they are free of microbe growth, that is to say can be provided for example preserved against microbe growth, preferably sterile.